Proteinreaktive Naturstoffe

Abstract

In der Post‐Genom‐Ära steht man vor der gewaltigen Aufgabe, die Strukturen und Funktionen zehntausender codierter Proteine zuzuweisen. Zur Analyse der Proteinfunktion werden neue Technologien mit großer Bandbreite entwickelt, etwa die aktivitätsbasierte Proteinanalyse (activity‐based protein profiling, ABPP). Bei diesem Verfahren sollen auf das aktive Zentrum gerichtete chemische Sonden entwickelt werden, um die Enzyme in ganzen Proteomen zu analysieren. Derartige chemische Proteomtechnologien können von proteinreaktiven Naturstoffen lernen, die Enzyme der unterschiedlichsten Klassen durch ein bemerkenswert vielfältiges Spektrum an Mechanismen kovalent modifizieren und somit eine reiche Quelle an Konzepten für die Entwicklung gegen aktive Zentren gerichteter Proteomsonden bilden. Hier werden wir anhand unterschiedlicher Naturstoffe zeigen, wie ihre Wirkmechanismen zum Fortschritt chemischer Proteomtechnologien wie ABPP beigetragen haben.

Design and Synthesis of a Tag‐Free Chemical Probe for Photoaffinity Labeling

“…[1,2] Also the target of an active compound, frequently a natural product, needs to be found. Depending on the nature of the ligand, activity-based profiling [3] or affinity chromatography can be used. However, in some cases like low-abundance proteins, recourse to photoaffinity labeling (PAL) has to be made.…”

Cytotoxic Polyketides Containing Tetramic Acid Moieties Isolated from the Fungus Myceliophthora Thermophila: Elucidation of the Relationship between Cytotoxicity and Stereoconfiguration

“…For instance, some natural products, such as lipstatin, lactacystin, and some l-trans-(S,S)-epoxysuccinic acids actively react with target enzymes to form covalent complexes. [16] Some reports of deoxy-tetramic acids [12,15] suggest that an intramolecular OH group or extraction and isolation solvent molecules can attack the b position of an a,b-unsaturated ketone by way of a Michael reaction during the biogenetic route or in the processes of isolation and purification to form artificial products. The mechanism of action of 1-5 is currently under investigation.…”

Modular Synthesis of Radicicol A and Related Resorcylic Acid Lactones, Potent Kinase Inhibitors

“…In addition to the therapeutic potential of this family of natural products, the irreversible nature of these inhibitors also offers a new lead structure for the design of selective inhibitors towards engineered kinases [25,26] as well as for chemical proteomics. [27] …”

“…The crude reaction mixtures were simply loaded on fluorous-silica columns and eluted first with 75 % MeOH in water to remove all non-fluorous-tagged components and then washed with MeOH to recover the desired compounds. All the compounds (21)(22)(23)(24)(25)(26)(27) came at the solvent front with the MeOH wash and could be recovered in excellent yields. Reactions that were performed under basic conditions (22 to 23 and alkylation with 24) were quenched with benzoic acid resin prior to loading on the column.…”